Abstract

5154

We have reported previously the development of a recombinant live-attenuated vaccine platform based on the intracellular bacterium Listeriamonocytogenes (Lm) as a vaccine platform a vector which induces potent CD4+ and CD8+ T cell responses specific for encoded heterologous antigens. Lm is a ubiquitous food-borne contaminant, and it is estimated that healthy adults in the U.S. ingest 105Lm four times per year. The use of other vaccine platforms for active immunotherapy such as viral vectors has shown that the existence of vector-specific immunity can result in neutralization after repeated administration or due to pre-existing immunity. For successful clinical application, it is important to characterize the impact of pre-existing Lm-specific immunity on priming as well as boosting of immune responses to the encoded heterologous antigens. We demonstrate here that in mice previously exposed to wild-type Lm, a single vaccination with recombinant Lm encoding ovalbumin or the endogenous mouse antigen gp70 could prime an antigen-specific CD8+ T cell response; however, this response was attenuated compared to the response measured in mice that were not exposed to Lm prior to vaccination. The reduction of primary antigen-specific immune response correlated inversely with the frequency of Lm-specific T cells found before vaccination with the recombinant Lm vaccine, which corresponded to the dose of wild-type Lm exposure. However, even after exposure to the highest dose of wild-type Lm, the ovalbumin- as well as gp70-specific responses could be boosted by a subsequent vaccination with recombinant Lm strains, even in pre-immune mice. Because significant Lm-specific antibodies were observed in mice immunized with attenuated Lm strains, we also assessed whether repeated administrations of Lm-based vaccines will be attenuated due to Lm-specific humoral immunity. Importantly, passive transfer of Lm-specific antibody to naïve mice did not reduce priming of a primary ovalbumin-specific cellular immune response in treated mice. We also demonstrate that the reduction in immunogenicity due to vector-specific immunity is much more dramatic with vaccinia virus-based vaccines as compared to Lm-based vaccines. Our findings suggest that the underlying immunity to Lm does not preclude priming or boosting of immune responses to recombinantly expressed heterologous antigens, and that Lm-based vaccines may represent a promising opportunity for cancer immunotherapy.